S-carboxyethyl-thioisosemicarbazones



Patented Mar. 16, 1954 S-CARBOXYETHYL-THIOISOSEMI- CARBAZON ES CharlesF. Huebner,

Morristown, N. 1., assignor to Ciba Pharmaceutical Products,Incorporated, L Summit, N. 3., a corporation of New Jersey No Drawing.Application May 3, 1951, Serial No. 224,453

This invention relates to certain S-carboxyethyl derivatives of aromaticaldehyde thioisosemicarbazones and to the preparation thereof.

A primary object of the present invention is the embodiment of a newgroup of compounds which are characterized by marked antitubercularactivity while at the same time exhibiting markedly lower toxicity thanthe comparable known prior art compounds. A further object of theinvention is the development of a process for the realization of suchembodiment.

These objects and others which will be evident from the followingspecification are realized (a) by the new substituted,3-(1-benzylidine-3-thlo 3-isosemicar'bazide)-propionic acids andsubstituted fi-(l-benzylidine-S-thio 3 isosemicarbazide) -ethanesulfonic acids of the present invention which correspond to the formulaXYCH=N-N=( JSCHaCH2-Z wherein Y is a benzene nucleus and X is alkoxy (e.g. methoxy, ethoxy, propoxy, etc.) or acylamino (e. g. acetamido,propionamido, butyramido, etc.) attached to one of the meta and parapositions of Y, and methylenedioxy attached to the meta-para positionsof Y, and Z is carboxyl (COOH) or sulfonyl (SO3H) and by theWater-soluble salts of the said new compounds with either acids orbases, and (b) by the preparation of the said compounds by reacting anappropriate aromatic aldehyde thiosemicarbazone with a reactive ester offi-hydroxy-propionic acid, namely, p-propiolactone, ,B-bromo-propionicacid or p-iodo-propionic acid, or with a similar reactive ester ofb-hydroxyethane-sulfonic acid, in a polar solvent such as alcohol,dioxane and the like.

The reaction scheme for the process of preparation of the aforesaid newcompounds according to the present invention is as follows:

wherein X, Y and Z have the previously-indicated significance-s. Thereaction is carried out conveniently at elevated temperatures, such asthe reflux temperatures of the solvents employed. After the reaction iscompleted, the solvent is evaporated off and the residue treated with anaqueous solution of a weak alkali, such as sodium bicarbonate, whereuponunreacted starting ma- 6 Claims. (Cl. 260340.5)

terial is removed by filtration. The filtrate is then neutralized with aweak acid such as acetic acid, whereupon the amino acid is precipitatedand for further purification is recrystallized from a lower aliphaticalcohol. The products may be used in this form as a therapeutic agent inview of their antitubercular activity or, if desired, advantage may betaken of their capacity for forming water-soluble salts, in which eventthey may be converted into salt form with the aid of appropriate acidssuch as hydrochloric, citric, maleic, sulfuric, phosphoric,ethanesulfonic, etc., whereby the corresponding hydrochloride, citrate,maleate, sulfate, phosphate, ethanesulfonate, etc. is formed, or withthe aid of appropriate bases such as the hydroxides of the alkali metals(e. g. sodium, potassium) or alkaline earth (e. g. magnesium) metals,whereby the corresponding metal salts are formed.

In many instances, the product will crystallize from the reactionmixture when the latter is refrigerated. In such cases, the solvent isremoved by filtration rather than evaporation, and the residue treatedas precedingly'described.

The invention is illustrated in greater detail in the examples whichfollow and which are presented by Way of illustration only and not byway of limitation. In these examples, parts by weight bear the samerelation to parts by volume as do grams to milliliters. Temperatures areexpressed in degrees centigrade and all melting points are uncorrected.

Example 1 A mixture of 50 parts by weight ofl-(l-acetamido-benzyaldehyde) -3-thiosemicarbazone,

NH: and 15.5 parts by weight of p-propiolactone,

C H2CH2 C O is refluxed in 500 parts by volume of ethanol for 3 hours.After refrigeration overnight, the formed crude amino acid is filtered.To separate the product from a small amount of unreactedthiosemicarbazone, the crude product is suspended in 200 parts by volumeof water containing 20 parts by weight of sodium bicarbonate, and themixture warmed to 50 for a few minutes. The amino acid dissolves as thesodium salt, and the undissolved thiosemicarbazone is removed byfiltration. Neutralization of the 3 cooled filtrate with acetic acid (pHabout 6) results in the crystallization of pure13-[1-(4-acetamido-benzylidine) 3 thio 3 isosemicarbazidel-propionicacid:

in the form of the dihydrate. The substance is recrystallized fromwater, whereupon its melting point is 122-125 (with decomposition).Thehydrochloride, which melts at 210-211 (with decomposition), isprepared by warming the amino acid in an equivalent of S-normalhydrochloric acid and then cooling. freely soluble in water (pH Anaqueous solution of the sodium salt is prepared by warming the aminoacid with one molar equivalent of so dium bicarbonate (pH 8) Example 2 Amixture of 10 parts by weight of anisaldehyde thiosemicarbazone and 4.5parts by weight of B-propiolactone is refluxed in 50 parts by volume ofethanol for minutes. On cooling, the formed amino acid crystallizes out.It is purified by the bicarbonate treatment, described in Example 1. The,6-(1-anisylidine-3-thio-3isosemicarbazide) propionic acid:

thus obtained is recrystallized from ethanol and melts at 110 (withdecomposition). The hydrochloride is prepared as described in Example 1and melts at 198-199 (with'deoomposition) after it has beenrecrystallized from ethanol.

Example 3 By replacing the anisaldehyde thiosemicarbazone of Example 2by an equivalent quantity of 4-ethoxy-benzaldehyde thiosemicarbazone andotherwise proceeding as described in the said example, the corresponding8-[1- (4-ethoxy-benzylidine)-3-thio 3 isosemicarbazidel -propionic acid:

which melts at 137-139 (with decomposition), is obtained.

Example 4 By replacing the anisaldehyde thiosemicarbazone of Example 2by an equivalent quantity of 3-ethoxy-benzaldehyde thiosemicarbazone andotherwise proceeding as described in the said example, the corresponding5-[1-(3-ethoxy-benzylidine) 3 thio 3 isosemicarbazide]-propionio acid:

I NH: 0 (32115 which melts at 98-102 (with decomposition), is obtained.

Byusing a 3-methoxy-benzaldehyde thiosemicarbazone, the corresponding3-methoxy derivative The hydrochloride is Example 5 Example 6 By using3.8 parts by weight of s-iodo-propionic acid .in place of the 2.9 partsby weight of 5- bromo-propionic acid of Example 5 and otherwiseproceeding as described in the said example, the

identical productB-(anisylidine 3 thio-3-isosemicarbazide) -propionicacid-is obtained.

Example 7 A mixture of 20 parts by weight of pipero'naldehyde (3,4methylenedioxybenzaldehyde) thiosemicarbazone and 6.5 parts by weight ofe-propiolactone is refluxed for 30 minutes in parts by volume ofacetone, then cooled. and the obtained crystals of B-(1-piperonylidine3-thio- 3-isosemicarbazide) -propionic acid:

recrystallized fom ethanol; they melt at 218-220 (with decomposition).

Example 8 A mixture of 3 parts by weightof anisaldehydethiosemicarbazone and 2.8 parts by weight of sodiumB-bromo-ethanesulfonate BrCH2CI-I2SOaNa) is refluxed for 6' hours in 30parts by volume of ethanol to which 1.1 parts by volume of concentratedhydrochloric acid has been added. The solids which separate on coolingare filtered off. and purified by the bicarbonate treatment de scribedin Example 1-. Insoluble by-prod'uctandv starting material are removedby filtration and, on the addition of acetic acid to the filtrate, 5(21- anisylidine-3-thio-3-isosemicarbazide) ethanesulfonic acidseparates as the monohydrate. After recrystalrlization from water, thelatter melts at 181-184 (with decomposition) Having thus disclosed theinvention, what is claimed is:

1. B 1 (4 acetamido benzylidine) 3 thio-3-isosemicarbazide]-propionicacid of the formula 2. p (1 anisylidine 3=- thio 3 isosemicarbazide)-propionic acid of the formula 5 3. B (1 piperonylidine 3 thio 3isosemicarbazide) -propionic acid of the formula CH=NN=(I"J-SOH:CH:COOH

4. 13-[1 (4 ethoxy benzylidine) 3 thio 3-isosemioarbazide] -propionicacid of the formula NH: 5. 5- [1- (3-methoxy-benzylidine)-3-thio-3-isosemicarbazidel -propionic acid of the formula 6. A memberof the group consisting of a compound of the formula the water-solublenon-toxic salts thereof with acids, and the water-soluble non-toxicalkali metal and alkaline earth metal salts thereof,

References Cited in the file of this patent UNITED STATES PATENTS NumberName Date 2,474,838 Gresham et a1 July 5, 1949 FOREIGN PATENTS NumberCountry Date 76,219 Germany 1949 OTHER. REFERENCES Baird et al.: "J.Chem. Soc. (London), 1927, pp. 2527-34.

Beinstein et al.: J. Am. Chem. Soc.," vol. '73, Mar. 1951, pp. 906-912(presented Am. Chem. Soc. 117th meeting, Apr. 9-13, 1950).

3. B - (1 - PIPERONYLIDINE - 3 - ISOSEMICARBAZIDE)-PROPIONIC ACID OF THEFORMULA
 6. A MEMBER OF THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA